Roles of the PI-3K and MEK pathways in Ras-mediated chemoresistance in breast cancer cells

Br J Cancer. 2003 Jul 7;89(1):185-91. doi: 10.1038/sj.bjc.6601048.

Abstract

Activated Ras utilises several downstream pathways, including the mitogen-activated protein kinase (MAPK) kinase (MEK)/MAPK pathway and the phosphoinositide 3-kinase (PI-3k)/Akt pathway, to promote cell proliferation and to inhibit apoptosis. To investigate which pathway plays a major role in Ras-induced drug resistance to chemotherapeutic agents in breast cancer cells, we transfected MCF7 breast cancer cells with a constitutively active H-RasG12V and examined the toxicities of three commonly used breast cancer chemotherapeutic agents, paclitaxel, doxorubicin, and 5-fluorouracil in these cells under the conditions that PI-3K or MEK were selectively inhibited by their respective specific inhibitors or dominant negative expression vectors. We found that Ras-mediated drug resistance is well correlated with resistance to apoptosis induced by anticancer agents in MCF7 breast cancer cells. Although inhibition of MEK/MAPK or PI-3K/Akt can each enhance the cytotoxicity of paclitaxel, doxorubicin, or 5-fluorouracil, inhibition of the PI-3K/Akt pathway seems to have a greater effect than inhibition of the MEK/MAPK pathway in reversing Ras-mediated drug resistance. Our results indicate that the PI-3K pathway may play a more important role in receptor tyrosine kinase-mediated resistance to chemotherapy and suggest that PI-3K/Akt might be a critical target molecule for anticancer intervention in breast cancer.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Apoptosis
  • Breast Neoplasms / pathology*
  • Drug Resistance, Neoplasm / physiology*
  • Female
  • Humans
  • MAP Kinase Kinase Kinase 1*
  • Phosphatidylinositol 3-Kinases / pharmacology*
  • Protein-Serine-Threonine Kinases / pharmacology*
  • Tumor Cells, Cultured

Substances

  • Antineoplastic Agents
  • Phosphatidylinositol 3-Kinases
  • Protein-Serine-Threonine Kinases
  • MAP Kinase Kinase Kinase 1
  • MAP3K1 protein, human